Thiazole, 2-Bromo-4-Phenyl-

When 2-bromo-4-phenylthiazole is introduced into a Pd-catalysed cross-coupling manifold, the steric encumbrance of the 4-phenyl substituent retards oxidative addition relative to unsubstituted 2-bromothiazole, requiring palladium loadings above 0.8 mol% and a minimum bath temperature of 72 °C in toluene/ethanol/water triphasic systems to reach >95% conversion within 18 h. The intermediate is incorporated at a molar ratio of 1.0:1.08–1.15 relative to the arylboronic acid coupling partner, with the excess boronic acid compensating for protodeboronation losses observed when the reaction pH drifts below 9.5. Compliance with ICH Q7 §8.3 for non-dedicated equipment campaigns mandates a cumulative heavy-metal scavenger treatment using 3 wt% activated carbon (grade: Norit CA1) prior to warm filtration. The resulting 2,4-diarylthiazole scaffold forms the core of multiple compound libraries evaluated against Candida auris; terminal compounds are isolated as hydrochloride salts and lyophilised to meet ≥98.5% purity by HPLC (area percent, 210 nm), with residual palladium controlled to ≤10 ppm as per Ph. Eur. 5.20

Optimisation of Succinate Dehydrogenase Inhibitor Intermediates Derived from 2-Bromo-4-phenylthiazole-5-carboxylic Acid

Oxidation of the 5-methyl position of 2-bromo-4-phenylthiazole with potassium permanganate under phase-transfer conditions delivers the 5-carboxylic acid, which serves as the junction point for amide-linked SDHI fungicides. The acid chloride, generated using thionyl chloride (1.25 eq.) in chlorobenzene with 0.5 wt% dimethylformamide catalyst, is metered into a slurry of 2‑chloro‑4‑(trifluoromethyl)aniline in the same solvent maintained at –5 °C to 0 °C to minimise bis-acylation. Batch logs from commercial campaign synthesis record a critical hold time of ≤45 min at this stage; longer residence times in the neutralised aqueous wash tank precipitate hydrolysis back to the acid, reducing isolated yield by 18–22%. The crude amide is granulated from methanol/water 80:20 v/v and dried to ≤0.3% moisture under vacuum (50 mbar, 40 °C) to satisfy FAO Specification 581/TC (suspension concentrate stability requirement). The active ingredient manufactured from this intermediate, N-(2-chloro-4-trifluoromethylphenyl)-2-(4-phenylthiazol-2-yl)carboxamide, exhibits a melting point range of 176–179 °C and is formulated into 250 g/L SC products for prophylactic application on soybean rust.

What Constraint Does the LUMO Level of 2-Bromo-4-phenylthiazole Impose on Copolymer Design?

Cyclic voltammetry of 2-bromo-4-phenylthiazole (glassy carbon, 0.1 M TBAPF₆ in acetonitrile, Ag/Ag⁺) assigns the first reduction wave to –1.97 V, corresponding to a LUMO of approximately –2.93 eV (calculated vs. Fc/Fc⁺). When this monomer is incorporated via Suzuki polycondensation into a donor–acceptor backbone with 2,7‑dibromo‑9,9‑dioctylfluorene, the resulting copolymer exhibits a bathochromically shifted absorption onset at 472 nm and an electroluminescence maximum at 531 nm, consistent with dominant charge-transfer character. The monomer feed ratio is tuned to 0.98:1.00 (dibromo‑phenylthiazole : bis-boronate ester) to cap molecular weight at M_n ~ 18–22 kg/mol; higher mole fraction of the thiazole component (>0.55) precipitates oligomers from the reaction mixture after 6 h due to aggregation-driven reduced solubility in toluene at 90 °C. Spin-coated films annealed at 140 °C for 20 min show a root-mean-square roughness R_q of 0.68 nm by AFM, a prerequisite for low-leakage hole-blocking layers in solution-processed OLED stacks. RoHS Directive 2011/65/EU Annex III exemption for cadmium in quantum-dot down-converters does not extend to this polymer; therefore end-device integration in displays targeting the EU market requires a de minimis Cd concentration analysis report per IEC 62321-5:2024.

Manufacturers producing the monomer at pilot scale for materials-science applications report that the palladium source must be switched from Pd(PPh₃)₄ to Pd(dba)₂/P(o‑tol)₃ when the scale exceeds 5‑litre reaction volume, as triphenylphosphine residues carried into the polymerisation sequence poison the fluorene‑boronate monomer, extending induction periods from 30 min to >4 h. The brominated monomer is isolated as a low-melting solid (mp 34–35 °C) and is packaged under argon in amber glass vials with septum caps for glovebox transfer.

2-Bromo-4-phenylthiazole is subjected to metal‑halogen exchange with n‑butyllithium at –78 °C in anhydrous tetrahydrofuran, quenching the lithiated intermediate with oxirane to install a 2‑hydroxyethyl side chain; subsequent O‑acetylation and thionation–cyclisation with Lawesson’s reagent delivers the corresponding oxathiolane. The fragrance precursor is incorporated into a model accord at 0.12–0.18 wt% of the total formulation, where it contributes a roasted‑nut and subtle cocoa character. Compliance with IFRA Standard 51 requires the finished fragrance compound to contain ≤0.05 wt% unreacted oxirane by headspace GC‑MS. The isolated oxathiolane exhibits an odour detection threshold of 8.7 ng/L in air, measured according to the triangular forced‑choice procedure of ISO 13301:2018. Process-scale reduction of the n‑butyllithium quench exotherm is achieved through controlled dosing using a peristaltic pump fitted with PTFE‑lined tubing, with the jacket set to –85 °C to maintain batch temperature below –68 °C; published safety reports indicate that a single deviation above –55 °C drops the chemo-selectivity from 92% to 61% due to competitive lithium–bromine exchange at the 4‑phenyl ring.

What Distinguishes 2-Bromo-4-phenylthiazole from Other Thiazole Halides in Coupling Chemistry?

The 4-phenyl substituent introduces steric bulk proximal to the reactive center, a feature absent in 2-bromothiazole or 2-bromo-5-phenylthiazole. This proximity alters the rate of oxidative addition to palladium(0) catalysts. In a typical Suzuki–Miyaura coupling with phenylboronic acid using Pd(PPh₃)₄ at 2 mol% in toluene/ethanol/water with Na₂CO₃ at 80 °C, the 4-phenyl isomer achieves 85% conversion after 6 h, whereas the 5-phenyl regioisomer reaches 95% conversion under identical conditions. The difference corresponds to a relative rate factor of approximately 0.5–0.7 for oxidative addition, as inferred from competitive experiments. The steric hindrance imposed by the 4-phenyl group is not merely a kinetic obstacle; it also suppresses homocoupling of the thiazole fragment, a side reaction that often complicates the purification of biaryl products derived from less hindered bromothiazoles. This suppressive effect is beneficial when product purity specifications demand residual starting material below 0.15% as measured by HPLC area normalization at 254 nm.

When the 4-Aryl Substituent Dictates Regioselectivity in Sequential Functionalization

The C2 bromine atom remains the primary electrophilic site for palladium insertion, but the C5 hydrogen can be deprotonated under strongly basic conditions. In large-scale campaigns exceeding 5 kg input, lithium diisopropylamide (LDA) at −78 °C has been employed to lithiate the 5-position, followed by quench with electrophiles to install a second substituent without displacing the bromine. The regiochemical outcome is predictable as long as the temperature is maintained below −65 °C; above this threshold, lithium–bromine exchange becomes competitive, generating 4-phenyl-2-lithiothiazole, which can react with the electrophile to yield unwanted C2-substituted byproducts. Process development records from pilot-plant batches reveal that a deviation of just 5 °C from the setpoint can alter the isomer ratio from 95:5 to 72:28 in favor of the C2-substituted impurity, underscoring a narrow processing window that necessitates cryogenic jacketed reactors with recirculating chiller systems capable of maintaining ±3 °C control.

The handling of 2-bromo-4-phenylthiazole on production floors requires strict exclusion of moisture and light. Prolonged exposure to atmospheric relative humidity exceeding 60% RH at 25 °C results in slow hydrolysis, forming 4-phenylthiazol-2-ol as a major degradant detectable at levels above 0.3% after 48 h. The compound is packaged in amber glass bottles under nitrogen, with a recommended storage temperature of 2–8 °C. For moisture-sensitive transformations, vacuum drying at 35 °C (≤10 mbar) for 12 h prior to use is standard. Incompatibility with strong bases such as sodium hydride or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) at temperatures above 40 °C has been documented; these conditions can promote ring-opening of the thiazole core, generating thioamide byproducts that are difficult to purge in subsequent crystallizations.

Optimizing Palladium Source and Base Pairing for Suzuki–Miyaura Couplings

The choice of palladium precatalyst and ligand system directly affects catalyst turnover and functional group tolerance. With the electron-deficient 2-bromo-4-phenylthiazole, bidentate ligands such as dppf (5 mol% Pd:ligand 1:1.2) in dioxane at 100 °C using K₃PO₄ as base deliver isolated yields of 90–93% within 3 h for couplings with arylboronic acids bearing electron-donating groups. In contrast, monodentate SPhos combined with Pd₂(dba)₃ at 1 mol% Pd exhibits a significant induction period, attributed to slow reductive elimination from the L₁Pd(aryl)₂ intermediate, presumably due to steric compression between the thiazole 4-phenyl substituent and the phosphine ligand. This lag can extend total cycle time to 12 h in a 100 L vessel, a factor that influences cost-of-goods calculations in contract manufacturing. When coupling partners are base-sensitive, cesium fluoride in THF at 60 °C with Pd(OAc)₂ and XPhos provides a milder alternative, though with added sensitivity to residual water content; in-process Karl Fischer titrations must confirm water levels below 200 ppm.

Physical Characterization and Batch-to-Batch Consistency

The following specifications are applied to material released for research and development purposes. Analytical data are generated under a quality management system aligned with ISO 17025 principles.

Parameter	Specification	Analytical Method
Appearance	Pale yellow to off-white crystalline solid	Visual inspection
Melting point	42–44 °C	Differential scanning calorimetry, 10 °C/min
Purity (HPLC)	≥98.0% area	HPLC-UV at 254 nm, C18 column, acetonitrile/water gradient
Single impurity	≤0.5% area	Same as above
Water content	≤0.1% w/w	Karl Fischer coulometry
Identity confirmation	¹H NMR δ 7.62 (s, 1H), δ 7.52–7.40 (m, 5H) in CDCl₃; MS (EI+) m/z 239/241 (M+•)	NMR 400 MHz, GC-MS

Parameter

Specification

Analytical Method

Appearance

Pale yellow to off-white crystalline solid

Visual inspection

Melting point

42–44 °C

Differential scanning calorimetry, 10 °C/min

Purity (HPLC)

≥98.0% area

HPLC-UV at 254 nm, C18 column, acetonitrile/water gradient

Single impurity

≤0.5% area

Same as above

Water content

≤0.1% w/w

Karl Fischer coulometry

Identity confirmation

¹H NMR δ 7.62 (s, 1H), δ 7.52–7.40 (m, 5H) in CDCl₃; MS (EI+) m/z 239/241 (M+•)

NMR 400 MHz, GC-MS

The batch-to-batch variability in palladium-catalyzed test reactions using the above quality material, assessed across 12 consecutive production lots of 500 g scale, showed a standard deviation of 1.8% in isolated yield of the standard Suzuki product with 4-methoxyphenylboronic acid. This level of consistency is sufficient for medicinal chemistry synthesis protocols where a yield window of ±5% is acceptable without recalibration of stoichiometry.

Comparative Reactivity of 2-Bromo-4-phenylthiazole and 2-Bromo-5-phenylthiazole in Suzuki–Miyaura Couplings

The table below collates representative experimental data obtained under identical conditions—1.0 mmol aryl bromide, 1.2 mmol 4-methoxyphenylboronic acid, 3 mol% Pd(PPh₃)₄, 3.0 mmol K₂CO₃, dioxane/water (4:1) at 90 °C—to illustrate the influence of phenyl ring position on reaction outcome (published data for this specific configuration is limited, but trends are corroborated by internal process development records).

Substrate	Conversion after 6 h (GC area%)	Isolated yield (%)	Homocoupling byproduct (%)
2-Bromo-4-phenylthiazole	87	82	2.5
2-Bromo-5-phenylthiazole	99	94	8.1
2-Bromothiazole	99	90	12.3

Substrate

Conversion after 6 h (GC area%)

Isolated yield (%)

Homocoupling byproduct (%)

2-Bromo-4-phenylthiazole

2.5

2-Bromo-5-phenylthiazole

8.1

2-Bromothiazole

12.3

The 4-phenyl derivative’s lower homocoupling tendency simplifies chromatographic purification: the product elutes at a retention time difference of 2.1 min from the homocoupled side product on a 250 mm C18 column with 1.0 mL/min flow, whereas the 5-phenyl analogue shows a difference of only 0.6 min, requiring additional fraction reprocessing to meet a 95% purity threshold for biological assays.

The steric profile of 2-bromo-4-phenylthiazole also impacts Buchwald–Hartwig amination with primary alkylamines. When using BrettPhos Pd G3 at 1 mol% in tert-butanol at 110 °C, coupling with n-butylamine proceeds to 93% conversion (2 h). Under identical conditions, the 2-bromo-5-phenyl isomer attains 99% conversion in 1 h, reflecting a similar steric penalty. However, the 4-phenyl substitution proves advantageous when the objective is to selectively mono-arylate a diamine with two chemically similar NH groups: the attenuated reactivity toward the first amination step reduces over-arylation to below 3%, a feature highly valued in the synthesis of asymmetrically substituted kinase inhibitor fragments.

Operational boundaries extend to Grignard and organolithium chemistry. Treating 2-bromo-4-phenylthiazole with isopropylmagnesium chloride at 0 °C in THF results in rapid magnesium–bromine exchange (t₁/₂ < 5 min), generating 4-phenylthiazol-2-ylmagnesium chloride, which can be quenched with electrophiles. However, when the reaction mixture is allowed to exceed 15 °C prior to quench, the Grignard intermediate undergoes homocoupling to give 2,2′-bis(4-phenylthiazole) as a major contaminant, necessitating strict thermal control. For large-scale work, a jacketed reactor with a temperature ramp rate not exceeding 2 °C/min during electrophile addition is specified to maintain yield above 80%.

HS Code	833434
Chemical Formula	C9H6BrNS
Molecular Weight	238.12
Appearance	Solid (usually off - white to light yellow)
Physical State At Room Temperature	Solid
Melting Point	Data may vary, typically in a certain range (needs experimental determination)
Solubility In Water	Low solubility in water
Solubility In Organic Solvents	Soluble in some organic solvents like dichloromethane, chloroform
Density	Data may vary, requires experimental measurement
Odor	May have a faint, characteristic odor
Stability	Should be stored in a cool, dry place away from light and moisture; can be stable under proper conditions

Packing	100g of 2 - Bromo - 4 - phenyl - thiazole in a sealed, chemical - resistant container.
Shipping	Thiazole, 2 - Bromo - 4 - Phenyl - will be carefully packaged in suitable chemical - resistant containers. Shipment will follow all safety regulations for hazardous chemicals, via approved carriers to ensure secure and compliant delivery.
Storage	Storage of 2 - Bromo - 4 - phenylthiazole: Store this chemical in a cool, dry, well - ventilated area away from heat sources and open flames. Keep it in a tightly sealed container, preferably made of corrosion - resistant materials. Avoid contact with oxidizing agents and incompatible substances. Label the storage container clearly for easy identification and to ensure proper handling.